Remedy for hormone-dependent cancer

ABSTRACT

A therapeutic agent for a hormone-dependent cancer, which comprises (a) a steroid-sulfatase inhibitor and (b) an agent for hormone therapy and/or an agent for chemotherapy, which may be administered together or separately at an interval, is provided. A method for treating a hormone-dependent cancer, which comprises administering (a) a steroid-sulfatase inhibitor and (b) an agent for hormone therapy and/or an agent for chemotherapy together or separately at an interval, is also provided. A steroid-sulfatase inhibitor which is used in combination with an agent for hormone therapy and/or an agent for chemotherapy, and which is administered together therewith or separately therefrom at an interval, is also provided. A kit for treating a hormone-dependent cancer, which comprises a first component comprising (a) a steroid-sulfatase inhibitor and a second component comprising (b) an agent for hormone therapy and/or an agent for chemotherapy, is also provided. A pharmaceutical composition, which comprises (a) a steroid-sulfatase inhibitor and (b) an agent for hormone therapy and/or an agent for chemotherapy, is also provided. Further, use of (a) a steroid-sulfatase inhibitor and (b) an agent for hormone therapy and/or an agent for chemotherapy for the manufacture of a therapeutic agent for a hormone-dependent cancer is provided.

TECHNICAL FIELD

The present invention relates to a therapeutic agent for ahormone-dependent cancer, comprising a steroid-sulfatase inhibitor.

BACKGROUND ART

Among cancers, there are those wherein proliferation thereof is promotedby hormone(s) (hormone-dependent cancers). Such hormone-dependentcancers include breast cancer, ovarian cancer, endometrial dancer,prostatic cancer, and thyroid cancer.

Nowadays, the hormone-dependent cancers are treated by surgical removalof an organ that secretes a particular hormone (e.g. surgical removal ofthe ovary), by the administration of an inhibitor that reduces hormoneactivities in order to suppress the proliferation of thehormone-dependent cancer cells (e.g. hormone therapy and chemotherapy),or the like. In some cases, these therapies may be performed incombination.

Examples of the agents for hormone therapy include antiestrogen agents,aromatase inhibitors, antiandrogen agents, preparations comprisingprogesterone, and preparations comprising an luteinizinghormone-releasing hormone (LH-RH) agonist.

On the other hand, steroid sulfatase is a hydrolase that convertsestrone sulfate, i.e. inactive estrogen, to estrone, i.e. activeestrogen, and that converts androstenediol sulfate, i.e. inactiveandrogen, to androstenediol, i.e. active androgen. Thus, steroidsulfatase is involved in the proliferation of mammary gland epithelialcells, hormone-dependent cancer cells or tumor cells.

A high estrogen level in breast cancer is considered to be caused by thehydrolysis of estrone sulfate to estrone by steroid sulfatase (estronesulfatase). Therefore, steroid-sulfatase inhibitors are considered to beeffective therapeutic agents for the treatment of estrogen-dependentbreast cancer (a hormone-dependent cancer), and further to be effectivefor preventing or treating other diseases in which estrones areconsidered to be involved, e.g. endometrial cancer, ovarian cancer,endometriosis, and adenomyosis uteri. Further, since steroid sulfataseis also involved in the biosynthetic process of androgen, it isconsidered to be effective for preventing or treating diseases in whichandrogens are considered to be involved, e.g. prostatic cancer.

It has been reported that estrone-3-sulfamate (EMATE) is a typicalinhibitor of steroid sulfatase (See, e.g. U.S. Pat. No. 5,616,574;International Journal of Cancer, 1995, 63: 106-111). However, it hasbeen shown that EMATE is not effective in the treatment ofestrone-dependent diseases because of its estrogen-like activity (See,e.g. Cancer Research, 1996, 56: 4950-4955).

So far, a large number of steroid-sulfatase inhibitors have been found(See, e.g. U.S. Pat. No. 5,830,886; WO98/11124; WO98/32763; ExpertOpinion on Therapeutic Patents, 1999, 9: 1083).

Such inhibitors include tyramine derivatives (See, e.g. U.S. Pat. No.5,567,831; Cancer Research, 1997, 57: 702-707; The Journal of SteroidBiochemistry and Molecular Biology, 1996, 59: 41-48; The Journal ofSteroid Biochemistry and Molecular Biology, 1999, 68: 31-40; The Journalof Steroid Biochemistry and Molecular Biology, 1999, 69: 227-238),cinnamic acid derivatives (See, e.g. U.S. Pat. No. 6,011,024.), anddiethylstilbestrol derivatives (See, e.g. The Journal of SteroidBiochemistry and Molecular Biology, 1999, 69: 227-238). Recently, othersteroid-sulfatase inhibitors have been disclosed (See, e.g. WO01/04086;WO01/02349).

Furthermore, estrone-3-methylthiophosphonate,estrone-3-methylphosphonate, estrone-3-phenylphosphonothioate,estrone-3-phenylphosphonate (See, e.g. U.S. Pat. No. 5,604,215; CancerResearch, 1993, 53: 298-303; Bioorganic & Medicinal Chemistry Letters,1993, 3: 313-318), and 3-monoalkylthiophosphate derivatives (See, e.g.WO91/13083) have been disclosed as steroid-sulfatase inhibitors.

In addition to the above, other steroid-sulfatase inhibitors have beendisclosed (See, e.g. WO93/05064; WO97/30041; WO99/33858; WO99/52890;WO01/36398; WO00/43408).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a therapeutic agent fora hormone-dependent cancer, which comprises a steroid-sulfataseinhibitor, and an agent for hormone therapy and/or an agent forchemotherapy, and the like.

The present invention relates to the following (1) to (36):

(1) A therapeutic agent for a hormone-dependent cancer, which comprises(a) a steroid-sulfatase inhibitor and (b) an agent for hormone therapyand/or an agent for chemotherapy, which may be administered together orseparately at an interval.

(2) A method for treating a hormone-dependent cancer, which comprisesadministering (a) a steroid-sulfatase inhibitor and (b) an agent forhormone therapy and/or an agent for chemotherapy together or separatelyat an interval.

(3) A steroid-sulfatase inhibitor which is used in combination with anagent for hormone therapy and/or an agent for chemotherapy, and which isadministered together therewith or separately therefrom at an interval.

(4) A kit for treating a hormone-dependent cancer, which comprises afirst component comprising (a) a steroid-sulfatase inhibitor and asecond component comprising (b) an agent for hormone therapy and/or anagent for chemotherapy.

(5) A pharmaceutical composition, which comprises (a) asteroid-sulfatase inhibitor and (b) an agent for hormone therapy and/oran agent for chemotherapy.

(6) Use of (a) a steroid-sulfatase inhibitor and (b) an agent forhormone therapy and/or an agent for chemotherapy for the manufacture ofa therapeutic agent for a hormone-dependent cancer.

(7) The therapeutic agent for a hormone-dependent cancer according to(1), wherein the steroid-sulfatase inhibitor is a compositioncomprising, as an active ingredient, a compound represented by Formula(I) or a pharmaceutically acceptable salt thereof:

[wherein X represents a phosphorus atom or a sulfur atom, and when X isa phosphorus atom, Y is hydroxy, and when X is a sulfur atom, Y is oxo;R¹ represents a hydrogen atom, substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted aryl, or —NR³R⁴ (wherein R³and R⁴ may be the same or different and each represents a hydrogen atom,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted lower alkenyl, or substitutedor unsubstituted aryl, or R³ and R⁴ are combined together with theadjacent nitrogen atom thereto to form a substituted or unsubstitutedheterocyclic group); and —O—R² represents a monocyclic alcohol residueor a polycyclic alcohol residue].

(8) The method for treating a hormone-dependent cancer according to (2),wherein the steroid-sulfatase inhibitor is a composition comprising, asan active ingredient, the compound represented by Formula (I) describedin (7) or a pharmaceutically acceptable salt thereof.

(9) The steroid-sulfatase inhibitor according to (3), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (I) described in (7) ora pharmaceutically acceptable salt thereof.

(10) The kit for treating according to (4), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (I) described in (7) ora pharmaceutically acceptable salt thereof.

(11) The pharmaceutical composition according to (5), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (I) described in (7) ora pharmaceutically acceptable salt thereof.

(12) The use of (a) a steroid-sulfatase inhibitor and (b) an agent forhormone therapy and/or an agent for chemotherapy according to (6),wherein the steroid-sulfatase inhibitor is a composition comprising, asan active ingredient, the compound represented by Formula (I) describedin (7) or a pharmaceutically acceptable salt thereof.

(13) The therapeutic agent for a hormone-dependent cancer according to(1), wherein the steroid-sulfatase inhibitor is a compositioncomprising, as an active ingredient, a compound represented by Formula(IA) or a pharmaceutically acceptable salt thereof:

(wherein —O—R², R³, and R⁴ have the same meanings as defined above,respectively).

(14) The method for treating a hormone-dependent cancer according to(2), wherein the steroid-sulfatase inhibitor is a compositioncomprising, as an active ingredient, the compound represented by Formula(IA) described in (13) or a pharmaceutically acceptable salt thereof.

(15) The steroid-sulfatase inhibitor according to (3), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (IA) described in (13)or a pharmaceutically acceptable salt thereof.

(16) The kit for treating according to (4), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (IA) described in (13)or a pharmaceutically acceptable salt thereof.

(17) The pharmaceutical composition according to (5), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (IA) described in (13)or a pharmaceutically acceptable salt thereof.

(18) The use of (a) a steroid-sulfatase inhibitor and (b) an agent forhormone therapy and/or an agent for chemotherapy according to (6),wherein the steroid-sulfatase inhibitor is a composition comprising, asan active ingredient, the compound represented by Formula (IA) describedin (13) or a pharmaceutically acceptable salt thereof.

(19) The therapeutic agent for a hormone-dependent cancer according to(1), wherein the steroid-sulfatase inhibitor is a compositioncomprising, as an active ingredient, a compound represented by Formula(IB) or a pharmaceutically acceptable salt thereof:

[wherein R³ and R⁴ have the same meanings as defined above,respectively; R⁵ represents a hydrogen atom, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, —NR⁶R⁷ (wherein R⁶ and R⁷ may be thesame or different and each represents a hydrogen atom, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedaryl, or a substituted or unsubstituted heterocyclic group), —OR⁸(wherein R⁸ represents a hydrogen atom, substituted or unsubstitutedlower alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group), or —SR^(8A) (whereinR^(8A) has the same meaning as R⁸ defined above)].

(20) The method for treating a hormone-dependent cancer according to(2), wherein the steroid-sulfatase inhibitor is a compositioncomprising, as an active ingredient, the compound represented by Formula(IB) described in (19) or a pharmaceutically acceptable salt thereof.

(21) The steroid-sulfatase inhibitor according to (3), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (IB) described in (19)or a pharmaceutically acceptable salt thereof.

(22) The kit for treating according to (4), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (IB) described in (19)or a pharmaceutically acceptable salt thereof.

(23) The pharmaceutical composition according to (5), wherein thesteroid-sulfatase inhibitor is a composition comprising, as an activeingredient, the compound represented by Formula (IB) described in (19)or a pharmaceutically acceptable salt thereof.

(24) The use of (a) a steroid-sulfatase inhibitor and (b) an agent forhormone therapy and/or an agent for chemotherapy according to (6),wherein the steroid-sulfatase inhibitor is a composition comprising, asan active ingredient, the compound represented by Formula (IB) describedin (19) or a pharmaceutically acceptable salt thereof.

(25) The therapeutic agent for a hormone-dependent cancer according to(1), (7), (13), or (19), wherein the agent for hormone therapy is one ormore selected from the group consisting of an antiestrogen agent, anaromatase inhibitor, an antiandrogen agent, a preparation comprisingprogesterone, and a preparation comprising a luteinizinghormone-releasing hormone (LH-RH) agonist.

(26) The method for treating a hormone-dependent cancer according to(2), (8), (14), or (20), wherein the agent for hormone therapy is one ormore selected from the group consisting of an antiestrogen agent, anaromatase inhibitor, an antiandrogen agent, a preparation comprisingprogesterone, and a preparation comprising a LH-RH agonist.

(27) The steroid-sulfatase inhibitor according to (3), (9), (15), or(21), wherein the agent for hormone therapy is one or more selected fromthe group consisting of an antiestrogen agent, an aromatase inhibitor,an antiandrogen agent, a preparation comprising progesterone, and apreparation comprising a LH-RH agonist.

(28) The kit for treating according to (4), (10), (16), or (22), whereinthe agent for hormone therapy is one or more selected from the groupconsisting of an antiestrogen agent, an aromatase inhibitor, anantiandrogen agent, a preparation comprising progesterone, and apreparation comprising a LH-RH agonist.

(29) The pharmaceutical composition according to (5), (11), (17), or(23), wherein the agent for hormone therapy is one or more selected fromthe group consisting of an antiestrogen agent, an aromatase inhibitor,an antiandrogen agent, a preparation comprising progesterone, and apreparation comprising a LH-RH agonist.

(30) The use of (a) a steroid-sulfatase inhibitor and (b) an agent forhormone therapy and/or an agent for chemotherapy according to (6), (12),(18), or (24), wherein the agent for hormone therapy is one or moreselected from the group consisting of an antiestrogen agent, anaromatase inhibitor, an antiandrogen agent, a preparation comprisingprogesterone, and a preparation comprising a LH-RH agonist.

(31) The therapeutic agent for a hormone-dependent cancer according to(1), (7), (13), or (19), wherein the agent for hormone therapy is anantiestrogen agent and/or an aromatase inhibitor.

(32) The method for treating a hormone-dependent cancer according to(2), (8), (14), or (20), wherein the agent for hormone therapy is anantiestrogen agent and/or an aromatase inhibitor.

(33) The steroid-sulfatase inhibitor according to (3), (9), (15), or(21), wherein the agent for hormone therapy is an antiestrogen agentand/or an aromatase inhibitor.

(34) The kit for treating according to (4), (10), (16), or (22), whereinthe agent for hormone therapy is an antiestrogen agent and/or anaromatase inhibitor.

(35) The pharmaceutical composition according to (5), (11), (17), or(23), wherein the agent for hormone therapy is an antiestrogen agentand/or an aromatase inhibitor.

(36) The use of (a) a steroid-sulfatase inhibitor and (b) an agent forhormone therapy and/or an agent for chemotherapy according to (6), (12),(18), or (24), wherein the agent for hormone therapy is an antiestrogenagent and/or an aromatase inhibitor.

Any hormone-dependent cancer or tumor, in which cancer cells or tumorcells are stimulated to proliferate by a hormone, can be exemplified asthe hormone-dependent cancer treated in the present invention. Suchhormone-dependent cancers include breast cancer, ovarian cancer,endometrial cancer, prostatic cancer, and thyroid cancer.

Any steroid-sulfatase inhibitor, which can inhibit the steroid sulfataseactivity, can be used as the steroid-sulfatase inhibitor. Examples ofsuch steroid-sulfatase inhibitors include a composition comprising, asan active ingredient, a sulfonate ester, a phosphonate ester, asulfamate, or a thiophosphate of a monocyclic alcohol or a polycyclicalcohol, or the like or a pharmaceutically acceptable salt thereof.

Specifically, the composition which comprises, as an active ingredient,a compound represented by Formula (I) or a pharmaceutically acceptablesalt thereof and the like are exemplified:

[wherein X represents a phosphorus atom or a sulfur atom, and when X isa phosphorus atom, Y is hydroxy, and when X is a sulfur atom, Y is oxo;R¹ represents a hydrogen atom, substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted aryl, or —NR³R⁴ (wherein R³and R⁴ may be the same or different and each represents a hydrogen atom,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted lower alkenyl, or substitutedor unsubstituted aryl, or R³ and R⁴ are combined together with anadjacent nitrogen atom thereto to form a substituted or unsubstitutedheterocyclic group); and —O—R² represents a monocyclic alcohol residueor a polycyclic alcohol residue].

Among them, the composition which comprises, as an active ingredient, acompound represented by Formula (IA) or a pharmaceutically acceptablesalt thereof and the like are preferred:

(wherein —O—R², R³, and R⁴ have the same meanings as defined above,respectively). A composition which comprises, as an active ingredient, acompound represented by Formula (IB) or a pharmaceutically acceptablesalt thereof and the like are more preferred:

[wherein R³ and R⁴ have the same meanings as defined above,respectively; R⁵ represents a hydrogen atom, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, —NR⁶R⁷ (wherein R⁶ and R⁷ may be thesame or different and each represents a hydrogen atom, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedaryl, or a substituted or unsubstituted heterocyclic group), —OR⁸(wherein R⁸ represents a hydrogen atom, substituted or unsubstitutedlower alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group), or —SR^(8A) (whereinR^(8A) has the same meaning as R⁸ defined above)].

A compound represented by Formula (I) is referred to as Compound (I)hereinafter. Compounds represented by other Formula numbers are alsoreferred to in the same manner.

In the definition of each group in Formulae (I), (IA), and (IB), (i) themonocyclic and polycyclic alcohols constituting monocyclic or polycyclicalcohol residues include any monocyclic and polycyclic alcohol. Forexample, sulfate compounds (the hydroxyl group is replaced by a sulfategroup) corresponding to the alcohols that can be substrates of thesteroid sulfatase are preferred. Among them, sulfate compounds having aKm value of less than 50 μmol/L during incubation at pH 7.4 and 37° C.with an enzyme having a steroid sulfatase activity are more preferred.

Examples of the monocyclic alcohol include a substituted orunsubstituted heterocycle having hydroxy as one of substituents thereof[the heterocycle corresponds to a compound formed by adding one hydrogenatom to a heterocyclic group (x) described later; and substituents otherthan hydroxy of the substituted heterocycle correspond to substituentsof the substituted heterocyclic group (xii) described later], and asubstituted or unsubstituted phenol [substituents of the substitutedphenol correspond to substituents of substituted heterocyclic group(xii) described later]. Specific examples include tyramine amidederivatives, hydroxycinnamic acid derivatives, and the like.

Examples of the polycyclic alcohol include substituted or unsubstitutedfused rings. Examples of the fused ring include di- to penta-cyclicfused rings having 6 to 60 carbon atoms, preferably 6 to 30 carbon atomsand formed by condensing 3- to 8-membered rings having a hydroxyl groupas one of the substituents. Each ring may be saturated or unsaturatedand may include an element such as a nitrogen atom, an oxygen atom, anda sulfur atom. Specific examples include substituted or unsubstitutedsterols; tetrahydronaphthol derivatives; coumarin, chroman, orisoflavone derivatives each having a hydroxyl group as one ofsubstituents; and 4-hydroxytamoxifen derivatives. Substituents of thesubstituted fused ring and the substituted sterol correspond tosubstituents of substituted sterol (iii) described later.

(ii) Examples of the sterol include 3-sterol such as estrone, estradiol,estriol, and dehydroepiandrosterone.

(iii) Substituents of the substituted sterol described here may be thesame or different. The number of the substituents may be 1 to 3, andexamples of the substituents include halogen, nitro, cyano, azide,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocyclic group, —C(═X¹)R⁵ (wherein X¹represents an oxygen atom or a sulfur atom, R⁵ has the same meaning asdefined above), —NR⁹R¹⁰ (wherein R⁹ and R¹⁰ may be the same or differentand each represents a hydrogen atom, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted aryl, asubstituted or unsubstituted heterocyclic group, —C(═X²)R¹¹ (wherein X²and R¹¹ have the same meanings as X¹ and R⁵ defined above,respectively), or —SO₂R¹² [wherein R¹² represents substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedaryl, a substituted or unsubstituted heterocyclic group, —NR¹³R¹⁴(wherein R¹³ and R¹⁴ have the same meanings as R⁶ and R⁷ defined above,respectively), or —OR¹⁵ (wherein R¹⁵ has the same meaning as R⁸ definedabove)]}, —OR¹⁶ [wherein R¹⁶ represents a hydrogen atom, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedaryl, a substituted or unsubstituted heterocyclic group, or —SO₂R¹⁷(wherein R¹⁷ has the same meaning as R¹² defined above)], —S(O)_(m)R¹⁸(wherein m represents 0 or 1, R¹⁸ represents a hydrogen atom,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted aryl, or a substituted or unsubstituted heterocyclicgroup), or —SO₂R¹⁹ (wherein R¹⁹ has the same meaning as R¹² describedabove).

The halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl,aryl, and heterocyclic group mentioned here, have the same meanings asthe halogen (ix), lower alkyl (iv), cycloalkyl (vii), lower alkenyl (v),lower alkynyl (vi), aryl (viii), and heterocyclic group (x) definedlater, respectively. Substituents of the substituted lower alkyl,substituted lower alkenyl, and substituted lower alkynyl have the samemeanings as substituents of the substituted lower alkyl (xiii) definedlater, respectively, and substituents of the substituted cycloalkyl,substituted aryl, and substituted heterocyclic group have the samemeanings as substituents of the substituted cycloalkyl (xvi) definedlater, respectively.

Specifically, examples of the substituted sterol include substitutedsterol having hydroxy at 3-position, for example, substituted estronesuch as 2-hydroxyestrone, 2-methoxyestrone, 4-hydroxyestrone,6β-hydroxyestrone, 1α-hydroxyestrone, 15α-hydroxyestrone, and15β-hydroxyestrone; substituted estradiol such as2-hydroxy-17β-estradiol, 2-methoxy-17β-estradiol,4-hydroxy-17β-estradiol, 6α-hydroxy-17β-estradiol,7α-hydroxy-17β-estradiol, 16α-hydroxy-17α-estradiol,16β-hydroxy-17α-estradiol, 16β-hydroxy-17β-estradiol, 17α-estradiol,17β-estradiol, and 17α-ethynyl-17β-estradiol; substituted estriol suchas 2-hydroxyestriol, 2-methoxyestriol, 4-hydroxyestriol,6α-hydroxyestriol, and 7α-hydroxyestriol; and substituteddehydroepiandrosterone such as 6α-hydroxydehydroepiandrosterone,7α-hydroxydehydroepiandrosterone, 16αα-hydroxydehydroepiandrosterone,and 16β-hydroxydehydroepiandrosterone. These substituted sterol mayfurther have the above-mentioned substituents.

(iv) Examples of the lower alkyl include linear or branched alkyl having1 to 20 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,heptyl, octyl, isooctyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, and eicocyl.

(v) Examples of the lower alkenyl include linear or branched alkenylhaving 2 to 8 carbon atoms, e.g. vinyl, allyl, 1-propenyl, butenyl,pentenyl, hexenyl, heptenyl, and oct enyl.

(vi) Examples of the lower alkynyl include linear or branched alkynylhaving 2 to 8 carbon atoms, e.g. ethynyl, propynyl, butynyl, pentynyl,hexynyl, heptynyl, and octynyl.

(vii) Examples of the cycloalkyl include cycloalkyl having 3 to 8 carbonatoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl.

(viii) Examples of the aryl include aryl having 6 to 14 carbon atoms,e.g. phenyl, naphthyl, and anthryl.

(ix) Examples of the halogen include fluorine, chlorine, bromine, andiodine atoms.

(x) Examples of the heterocyclic group include an aliphatic heterocyclicgroup and an aromatic heterocyclic group.

Examples of the aliphatic heterocyclic group include a 5- or 6-memberedmonocyclic group containing at least one atom selected from a nitrogenatom, an oxygen atom, and a sulfur atom, and a bicyclic or tricyclicfused ring which is formed by condensation 3- to 8-membered rings andwhich contains at least one atom selected from a nitrogen atom, anoxygen atom, and a sulfur atom. Specific examples includetetrahydropyranyl, pyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidino,piperidyl, perhydroazepinyl, perhydroazocinyl, morpholino, morpholinyl,thiomorpholino, thiomorpholinyl, piperazinyl, homopiperazinyl,oxazolinyl, dioxolanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,indolinyl, 1-oxo-1,3-dihydroisoindolyl,1,1-dioxo-2,3-dihydrobenz[d]isothiazolyl, 2-pyrrolinyl, 2-pyrrolidonyl,3-pyrrolidonyl, 2-piperidonyl, 3-piperidonyl, 4-piperidonyl,perhydro-2-azepinonyl, perhydro-3-azepinonyl, perhydro-4-azepinonyl,2-thiazolidonyl, 4-thiazolidonyl, 2-oxazolidonyl, 4-oxazolidonyl,succinimide, glutarimide, hydantoinyl, thiazolidinedionyl,oxazolidinedionyl, and the like.

Examples of the aromatic heterocyclic group include a 5- or 6-memberedmonocyclic group containing at least one atom selected from an nitrogenatom, an oxygen atom, and a sulfur atoms, and bicyclic or tricyclicfused ring which is formed by condensation of 3- to 8-membered rings andcontains at least one atom selected from a nitrogen atom, an oxygenatom, and a sulfur atom. Specific examples include furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, furazanyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolinyl,phthalazinyl, purinyl, indolyl, isoindolyl, 2-pyridonyl, 4-pyridonyl,uracilyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl,1,3-dioxo-1,3-dihydroisoindolyl,1,1,3-trioxo-2,3-dihydrobenz[d]isothiazolyl, maleimido, phthalimido, andthe like.

(xi) Examples of the heterocyclic group formed together with theadjacent nitrogen atom may contain an oxygen atom, a sulfur atom, or anitrogen atom other than the adjacent nitrogen atom. Specific examplesinclude pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidino,homopiperidino, piperazinyl, homopiperazinyl, pyrazolidinyl, morpholino,thiomorpholino, tetrahydroquinolyl, tetrahydroisoquinolyl,octahydroquinolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl,purinyl, dihydroindolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolinyl,imidazolyl, and the like.

(xii) Substituents of the substituted heterocyclic group may be the sameor different. The number of the substituents is 1 to 3, and examples ofthe substituents include halogen, nitro, cyano, azido, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, —C(═X¹)R⁵ (wherein X¹ and R⁵ have thesame meanings as defined above, respectively), —NR⁹R¹⁰ (wherein R⁹ andR¹⁰ have the same meanings as defined above, respectively), —OR¹⁶(wherein R¹⁶ has the same meaning as defined above), —S(O)_(m)R¹⁸(wherein m and R¹⁸ have the same meanings as defined above,respectively), and —SO₂R¹⁹ (wherein R¹⁹ has the same meaning as definedabove).

The halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl,aryl, and heterocyclic group mentioned here, have the same meanings asthe halogen (ix), lower alkyl (iv), cycloalkyl (vii), lower alkenyl (v),lower alkynyl (vi), aryl (viii), and heterocyclic group (x) definedabove, respectively. The substituents of the substituted lower alkyl,substituted lower alkenyl, and substituted lower alkynyl have the samemeanings as substituents of the substituted lower alkyl (xiii) definedlater, respectively, and the substituents of the substituted cycloalkyl,substituted aryl, and substituted heterocyclic group have the samemeanings as substituents of the substituted cycloalkyl (xvi) definedlater, respectively.

(xiii) The substituents of the substituted lower alkyl, substitutedlower alkenyl, and substituted lower alkynyl may be the same ordifferent. The number of substituents is 1 to 3, and examples of thesubstituents include halogen, nitro, cyano, azido, lower alkenyl, loweralkadienyl, lower alkatrienyl, lower alkynyl, (lower alkoxy)loweralkoxy, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, a substituted or unsubstituted heterocyclic group,—C(═X^(1A))R^(5A) [wherein X^(1A) has the same meaning as X¹ definedabove, and R^(5A) represents a hydrogen atom, lower alkyl, substitutedor unsubstituted cycloalkyl, lower alkenyl, lower alkynyl, substitutedor unsubstituted aryl, a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroarylalkyl, —NR^(6A)R^(7A) (wherein R^(6A) and R^(7A)may be the same or different and each represents a hydrogen atom, loweralkyl, substituted or unsubstituted cycloalkyl, lower alkenyl,substituted or unsubstituted aryl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted aralkyl, or substitutedor unsubstituted heteroarylalkyl), —OR^(8A) (wherein R^(8A) represents ahydrogen atom, lower alkyl, substituted or unsubstituted cycloalkyl,lower alkenyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, substituted or unsubstituted aralkyl,or substituted or unsubstituted heteroarylalkyl), or —SR^(8Aa) (whereinR^(8Aa) has the same meaning as R^(8A) defined above)], —NR^(9A)R^(10A){wherein R^(9A) and R^(10A) may be the same or different and eachrepresents a hydrogen atom, lower alkyl, substituted or unsubstitutedcycloalkyl, lower alkenyl, substituted or unsubstituted aryl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl,—C(═X^(2A))R^(11A) (wherein X^(2A) and R^(11A) have the same meanings asX^(1A) and R^(4A) defined above, respectively), or —SO₂R^(12A) [whereinR^(12A) represents lower alkyl, substituted or unsubstituted cycloalkyl,lower alkenyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroarylalkyl, —NR^(13A)R^(14A) (whereinR^(13A) and R^(14A) have the same meanings as R^(6A) and R^(7A) definedabove, respectively), or —OR^(15A) (wherein R^(15A) has the same meaningas R^(8A) defined above)]}, —OR^(16A) [wherein R^(16A) represents ahydrogen atom, lower alkyl; substituted or unsubstituted cycloalkyl,lower alkenyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroarylalkyl, or —SO₂R^(17A) (whereinR^(17A) has the same meaning as R^(12A) defined above)],S(O)_(ma)R^(18A) (wherein ma represents 0 or 1, R^(18A) represents ahydrogen atom, lower alkyl, substituted or unsubstituted cycloalkyl,lower alkenyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, substituted or unsubstituted aralkyl,or substituted or unsubstituted heteroarylalkyl), or —SO₂R^(19A)(wherein R^(19A) has the same meaning as R^(12A) defined above).

The halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,aryl, and heterocyclic group mentioned here, have the same meanings asthe halogen (ix), lower alkyl (iv), lower alkenyl (v), lower alkynyl(vi), cycloalkyl (vii), aryl (viii), and heterocyclic group (x)described above, respectively. Examples of the lower alkadienyl (xiv)include alkadienyl having 4 to 8 carbon atoms, e.g. 1,3-butadienyl,1,3-pentadienyl, 1,3-hexadienyl, 2,4-hexadienyl, and 1,3-octadienyl.Examples of the lower alkatrienyl (xv) include alkatrienyl having 6 to 8carbon atoms, e.g. 1,3,5-hexatrienyl and 1,3,5-octatrienyl. A loweralkyl moiety of the (lower alkoxy)lower alkoxy has the same meaning asthe lower alkyl (iv) defined above. The alkylene moieties of the (loweralkoxy)lower alkoxy, aralkyl, and heteroarylalkyl have the same meaningsas the group formed by removing one hydrogen atom from lower alkyl (iv)defined above. Aryl moiety of the aralkyl group has the same meaning asthe aryl (viii) defined above, and heteroaryl moiety of theheteroarylalkyl has the same meaning as the aromatic heterocyclic groupin the heterocyclic group (x) defined above.

Substituents of the substituted cycloalkyl, substituted aryl,substituted heterocyclic, substituted aralkyl, and substitutedheteroarylalkyl mentioned here, have the same meanings as thesubstituents of the substituted cycloalkyl (xvi) defined later,respectively.

(xiv) The substituents of the substituted cycloalkyl, substituted aryl,and substituted heterocyclic group formed together with the adjacentnitrogen atom may be the same or different. The number of thesubstituents is 1 to 3, and examples of the substituents include loweralkyl, halogen, nitro, cyano, azido, lower alkenyl, lower alkadienyl,lower alkatrienyl, lower alkynyl, (lower alkoxy)lower alkoxy,cycloalkyl, aryl, 4-sulfamoyloxybenzyl, a heterocyclic group,—C(═X^(1B))R^(5B) [wherein X^(1B) has the same meaning as X¹ definedabove, and R^(5B) represents a hydrogen atom, lower alkyl, cycloalkyl,lower alkenyl, lower alkynyl, aryl, a heterocyclic group, —NR^(6B)R^(7B)(wherein R^(6B) and R^(7B) may be the same or different and eachrepresents a hydrogen atom, lower alkyl, cycloalkyl, lower alkenyl,aryl, or a heterocyclic group), —OR^(8Ba) (wherein R^(8B) represents ahydrogen atom, lower alkyl, cycloalkyl, lower alkenyl, aryl, or aheterocyclic group), or —SR^(8Ba) (wherein R^(8Ba) has the same meaningas R^(8B) defined above)], —NR^(9B)R^(10B) (wherein R^(9B) and R^(10B)may be the same or different and each represents a hydrogen atom, loweralkyl, cycloalkyl, lower alkenyl, aryl, a heterocyclic group,—C(═X^(2B))R^(11B) (wherein X^(2B) and R^(11B) have the same meanings asX^(1B) and R^(5B) defined above, respectively), or —SO₂R^(12B) [whereinR^(12B) represents lower alkyl, cycloalkyl, lower alkenyl, aryl, aheterocyclic group, —NR^(13B)R^(14B) (wherein R^(13B) and R^(14B) havethe same meanings as R^(6B) and R^(7B) defined above, respectively), or—OR^(15B) (wherein R^(15B) has the same meaning as R^(8B) definedabove)]}, —OR^(16B) [wherein R^(16B) represents a hydrogen atom, loweralkyl, cycloalkyl, lower alkenyl, aryl, a heterocyclic group, or—SO₂R^(17B) (wherein R^(17B) has the same meaning as R^(12B) definedabove)], —S(O)_(mb)R^(18B) (wherein mb is 0 or 1, R^(18B) represents ahydrogen atom, lower alkyl, cycloalkyl, lower alkenyl, aryl, or aheterocyclic group), or —SO₂R^(19B) (wherein R^(19B) has the samemeaning as R^(12B) defined above).

The halogen, lower alkyl, lower alkenyl, lower alkadienyl, loweralkatrienyl, lower alkynyl, cycloalkyl, aryl, and heterocyclic groupmentioned here, have the same meanings as the halogen (iX), lower alkyl(iv), lower alkenyl (v), lower alkadienyl (xiv), lower alkatrienyl (xv),lower alkynyl (vi), cycloalkyl (vii), aryl (viii), and heterocyclicgroup (x), respectively. Lower alkyl moiety of the (lower alkoxy)loweralkoxy has the same meaning as the lower alkyl (iv) defined above, andalkylene moiety of the (lower alkoxy)lower alkoxy has the same meaningas the group formed by removing one hydrogen atom from lower alkyl (iv)defined above.

Examples of production methods for the above-mentioned effectiveingredients in the steroid-sulfatase inhibitors according to the presentinvention will now be described.

For example, the following compounds are prepared according to therespective documents: estrone-3-methylthiophosphonate,estrone-3-methylphosphonate, estrone-3-phenylphosphonothioate, andestrone-3-phenylphosphonate [Cancer Research, vol. 53, p. 298 (1993);Bioorganic & Medicinal Chemistry Letters, vol. 3, p. 313 (1993); U.S.Pat. No. 5,604,215]; estrone-3-sulfamate derivatives [Journal ofMedicinal Chemistry, vol. 37, p. 219 (1994)];3-desoxyestrone-3-sulfonate derivatives [Steroids, vol. 58, p. 106(1993); The Journal of Steroid Biochemistry and Molecular Biology, vol.50, p. 261 (1994)]; 3-desoxyestrone-3-methylsulfonate derivatives[Steroids, vol. 60, p. 299 (1995)]; estrone-3-amino derivatives [TheJournal of Steroid Biochemistry and Molecular Biology, vol. 59, p. 83(1996); U.S. Pat. Nos. 5,571,933 and 5,866,603]; vitamin D₃ derivatives[The Journal of Steroid Biochemistry and Molecular Biology, vol. 48, p.563 (1994).]; dehydroepiandrosterone derivatives [The Journal of SteroidBiochemistry and Molecular Biology, vol. 45, p. 383 (1993);Biochemistry, 36: 2586 (1997)]; estrone-3-sulfamate modifications [TheJournal of Steroid Biochemistry and Molecular Biology, vol. 64, p. 269(1998); WO98/24802; WO98/32763]; 17-alkylestradiol derivatives[Bioorganic & Medicinal Chemistry Letters, vol. 8, p. 1891 (1998);Journal of Medicinal Chemistry, vol. 42, p. 2280 (1999)];3-substituted-D-homo-1,3,5,(10)-estratriene derivatives (WO98/11124;WO99/27935); estrone modifications [WO98/42729; WO99/27936; CanadianJournal of Physiology and Pharmacology vol. 76, p. 99 (1998)];17β-(N-alkylcarbamoyl)estra-1,3,5(10)-triene-3-sulfamate and17β-(N-alkanoylamino)estra-1,3,5(10)-triene-3-sulfamate [Steroids, vol.63, p. 425 (1998); WO99/03876]; estrone modifications at the 17-position(WO99/33858); tetrahydronaphthol derivatives [Journal of MedicinalChemistry, vol. 37, p. 219 (1994)]; 4-methylcoumarin-7-sulfamate [CancerResearch, vol. 56, p. 4950 (1996); WO97/30041]; tyramine derivatives andphenol derivatives [Cancer Research, vol. 57, p. 702 (1997);Biochemistry, vol. 36, p. 2586 (1997); The Journal of SteroidBiochemistry and Molecular Biology, vol. 68, p. 31 (1999); U.S. Pat. No.5,567,831]; flavonoid [The Journal of Steroid Biochemistry and MolecularBiology, vol. 63, p. 9 (1997); WO97/32872]; 4-hydroxytamoxifenderivatives [The Journal of Steroid Biochemistry and Molecular Biology,vol. 45, p. 383 (1993); Bioorganic & Medicinal Chemistry Letters, vol.9, p. 141 (1999)]; isoflavone derivatives [The Journal of SteroidBiochemistry and Molecular Biology, vol. 69, p. 227 (1999)]; and chromanderivatives (WO99/52890).

Furthermore, WO93/05064, WO01/02349, WO97/30041, WO01/36398, andWO00/43408 disclose compounds having a steroid-sulfatase inhibitingactivity that can be used in the present invention, and these compoundscan be prepared according to methods disclosed therein.

For hormone therapy, agents that can (a) inhibit the production ofestrogen or androgen, (b) block estrogen from binding to an estrogenreceptor, (c) block androgen from binding to an androgen receptor, or(d) inhibit the secretion of estrogen or luteinizing hormone may beused. Examples of these agents are antiestrogen agents, aromataseinhibitors, antiandrogen agents, LH-RH agonists, and progesteroneproducts, and they may be used alone or in combination.

Examples of the antiestrogen agents include compositions comprisingtamoxifen, ICI-182780 (trade name; Faslodex, generic name; fulvestrant),toremifene, or pharmaceutically acceptable salts thereof as activeingredients.

Examples of the aromatase inhibitors include compositions comprisingamino-glutathione, anastrozole, letrozole, exemestane, vorozole,fadrozole, or pharmaceutically acceptable salts thereof as activeingredients.

Examples of the antiandrogen agents include compositions comprisingflutamide, bicalutamide, nilutamide, cyproterone, or pharmaceuticallyacceptable salts thereof as active ingredients.

Examples of the LH-RH agonists include compositions comprisingluprolide, goserelin, or pharmaceutically acceptable salts thereof asactive ingredients.

Examples of the progesterone products include compositions comprisingmegestrol acetate, medroxyprogesterone acetate, or pharmaceuticallyacceptable salts thereof as active ingredients.

Examples of the chemotherapy agents include compositions comprisingadriamycin, cyclophosphamide, paclitaxel, docetaxel, vinorelbine,fluorouracil, irinotecan, methotrexate, or pharmaceutically acceptablesalts thereof as active ingredients.

The pharmaceutically acceptable salts of the effective ingredients thatconstitute the steroid-sulfatase inhibitors, agents for hormone therapy,and agents for chemotherapy are, for example, pharmaceuticallyacceptable acid addition salts, metal salts, ammonium salts, organicamine addition salts, and amino acid addition salts. Examples of theacid addition salts include inorganic acid salts, e.g. hydrochloride,sulfate, and phosphate; and organic acid salts, e.g. acetate, maleate,fumarate, tartrate, citrate, lactate, and succinate. Examples of themetal salts include alkali-metal salts, e.g. sodium salt and potassiumsalt; alkaline-earth metal salts, e.g. magnesium salts and calciumsalts; aluminium salts, and zinc salts. Examples of ammonium saltsinclude ammonium salts and tetramethylammonium salts. Examples oforganic amine addition salts include addition salts of morpholine andpiperidine. Examples of amino acid addition salts include addition saltsof lysine, glycine, phenylalanine, aspartic acid, and glutamic acid.

Steroid-sulfatase inhibitors and agents for hormone therapy and/oragents for chemotherapy agents used in therapeutic agents andpharmaceutical compositions for hormone-dependent cancers according tothe present invention may be administered alone or in combination aspreparations containing their active ingredients. Particularly, acombination of two to four preparations is preferable. When thepreparations are used or administered in combination, they may be usedor administered together or separately at an interval.

These preparations can be manufactured by a conventional process using apharmaceutically acceptable diluent, excipient, disintegrant, lubricant,binder, surfactant, water, saline, vegetable-oil solubilizer, isotonicagent, preservative, or antioxidant in addition to each activeingredient.

When the preparations are administered in combination, for example, afirst component comprising (a) the steroid-sulfatase inhibitor and asecond component comprising (b) the agent for hormone therapy and/oragent for chemotherapy are separately prepared as described above andmade into a kit. By utilizing such a kit, different preparations can beadministered together or separately at an interval to one subject by thesame route or different routes. The second component may be furtherseparated into several components, preferably, two or three components.

The kit is composed of at least two containers (e.g. vials, bags) andcontents (i.e. the first and second components). The material and theshape of the containers are not limited, but the containers must preventthe contents, i.e. the components, from degrading due to externaltemperature or light during the storage, and should be made from amaterial that does not elute its chemical constituents. The firstcomponent and the second component are administerable dosage forms so asto be administered through different routes (e.g. tubes) or the sameroute. A preferable example is a kit for injection. For example, thecontainers of the first and second components are formed to connect to abag containing an infusion solution so that each of the components ismixed with the infusion solution.

A method for treating hormone-dependent cancers according to the presentinvention can be performed similarly to the above-mentioned utilizationor administration of the steroid-sulfatase inhibitor and the agent forhormone therapy and/or agent for chemotherapy used as the therapeuticagent for hormone-dependent cancers. Namely, the method can be performedby preparing the steroid-sulfatase inhibitor and the agent for hormonetherapy and/or agent for chemotherapy so as to contain their activeingredients and by administering alone or in combination, preferably, ina combination of two to four preparations. When the preparations areadministered in combination, they may be administered together orseparately at an interval and may also be administered in the form of akit as described above.

The efficiency of hormone-dependent cancer treatment by the combinedadministration of a steroid-sulfatase inhibitor and an agent for hormonetherapy will be explained in detail by referring to ExperimentalExamples.

EXPERIMENTAL EXAMPLE 1 Proliferation Inhibition of Breast Cancer CellsUsing Combination of Antiestrogen Agent and Steroid-Sulfatase Inhibitor

(1) MCS-2 cell in which human steroid-sulfatase is excessivelyexpressed, was established from human breast cancer cell (MCF-7).Inhibition of the MCS-2 cell proliferation by an antiestrogen agentalone or a steroid-sulfatase inhibitor alone was compared with that by acombination of the steroid-sulfatase inhibitor and the antiestrogenagent. ICI-182780 was used as the antiestrogen agent, and compound 1 wasused as the steroid-sulfatase inhibitor.

The MCS-2 cells were subcultured in a Phenol Red-free Eagle's minimumessential medium [PR(−)MEM; Nissui Pharmaceutical Co., Ltd.: referred toas medium A hereinafter] containing 5% bovine fetal serum (HyCloneLaboratories Inc.) treated with dextran-charcoal, 1 mmol/L sodiumpyruvate (Wako Pure Chemical Industries, Ltd.), 1% nonessential aminoacid (NEAA; Dainippon Pharmaceutical Co., Ltd.), 2 mmol/L L-glutamine(GIBCO BRL), and 0.11% sodium hydrogencarbonate solution (ICNBiomedicals Inc.).

A dimethylsulfoxide (DMSO; Kanto Kagaku) solution containing 10 mmol/Lestrone sulfate (Sigma Corp.) was diluted with medium A to a finalconcentration of 10⁻⁸ mol/L (medium B).

MCS-2 cells were diluted with the medium B containing estrone sulfate(final concentration: 10⁻⁸ mol/L) to a concentration of 2.5×10⁴ cells/mLand inoculated in a 96-well microtiter plate (NUNC) in an amount of 100μL/well. The plate was incubated in an incubator set at 37° C. and ahumidity of 95% or more in a 5%-CO₂ atmosphere for 24 hours, and thenthe medium was replaced with fresh estrone sulfate-containing medium Bor fresh estrone sulfate-free medium A. To each well in which the mediumwas replaced with fresh estrone sulfate-containing medium B, testcompound [(i) antiestrogen agent alone, (ii) a steroid-sulfataseinhibitor alone, or (iii) a combination of the antiestrogen agent andthe steroid-sulfatase inhibitor: these agents were sequentially dilutedwith medium A] was added. To each well in which the medium was replacedwith fresh estrone sulfate-free medium A, the agent was not added [(iv)agent-free]. The plate was incubated in an incubator set at 37° C. and ahumidity of 95% or more in a 5%-CO₂ atmosphere for 168 hours. After theincubation, the supernatant was carefully removed such that all thecells retained. Then, an MTT solution, which was prepared by dissolving3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (SigmaCorp.) in estrone sulfate-free medium A into a final concentration of0.5 mg/mL, was added to each well in an amount of 50 μL/well. The platewas incubated in an incubator set at 37° C. in a 5%-CO₂ atmosphere for 4hours. After the MTT solution was removed, 0.1 mL of DMSO was added toeach well. The plate was stirred with a plate mixer (Micro Mixer ModelMX-4; Sanko Junyaku Co., Ltd.), and the formed formazan was eluted tomeasure the difference in absorbance at 550 nm and 630 nm with a platereader (Spectra MAX 250; Wako Pure Chemical Industries, Ltd.). Theresults of inhibition of MCS-2 cell proliferation were indicated by arelative value of the number of MCS-2 cells in each condition to that inthe agent-free condition, and are shown as a relative value (%) of eachabsorbance (MTT assay).

FIG. 1 shows inhibition curves on the MCS-2 cell proliferation underconstant ICI-182780 concentrations while the concentration of Compound 1was varied. FIG. 2 shows inhibition curves on the MCS-2 cellproliferation under constant Compound 1 concentrations while theconcentration of ICI-182780 was varied.

As shown in FIG. 1, the inhibition of MCS-2 cell proliferation byCompound 1 was facilitated by the addition of ICI-182780 at aconcentration of 0.234 nmol/L or more as compared with the results ofthe case ICI-182780 was not added.

As shown in FIG. 2, the inhibition of MCS-2 cell proliferation byICI-182780 was facilitated by the addition of Compound 1 at aconcentration of 0.140 nmol/L or more as compared with the results ofthe case Compound 1 was not added.

(2) In order to evaluate the efficacy of the combination treatment withthe antiestrogen agent and the steroid-sulfatase inhibitor, anisobologram was constructed from the inhibition curves on the MCS-2 cellproliferation shown in FIGS. 1 and 2 according to International Journalof Radiation Oncology Biology Physics, page 85 (1979) and page 1145(1979).

When the antiestrogen agent or the steroid-sulfatase inhibitor was usedalone, the concentrations of each required to inhibit the proliferationof MCS-2 cells, i.e. the concentrations required to inhibit 50% of theproliferation (IC₅₀ value), inhibit 45% of the proliferation (IC₄₅value), inhibit 40% of the proliferation (IC₄₀ value), inhibit 35% ofthe proliferation (IC₃₅ value), inhibit 30% of the proliferation (IC₃₀value), inhibit 25% of the proliferation (IC₂₅ value), inhibit 20% ofthe proliferation (IC₂₀ value), inhibit 15% of the proliferation (IC₁₅value), inhibit 10% of the proliferation (IC₃₀ value), and inhibit 5% ofthe proliferation (IC₅ value), were calculated from the inhibitioncurves on the MCS-2 cell proliferation shown in FIGS. 1 and 2 in theabove-mentioned (1) with measurement software (the equation used in SoftMax Pro) equipped with a plate reader. An isobologram for IC₅₀ valueswas constructed using these IC₅ to IC₅₀ values according to theabove-mentioned paper. The isobologram is shown in FIG. 3.

(3) In order to evaluate the efficacy of the combination treatment, eachconcentration of the agents showing IC₅₀ values in combination was(plotted on the isobologram shown in FIG. 3 according to a methoddescribed in International Journal of Radiation Oncology BiologyPhysics, page 85 (1979) and page 1145 (1979).

IC₅₀ values under the conditions where ICI-182780 concentrations wereconstant, i.e. concentrations of Compound 1 when 50% of theproliferation of MCS-2 cells was inhibited, were plotted on theisobologram (FIG. 3) constructed in the above-mentioned (2). The resultsare shown in FIG. 4. IC₅₀ values under the conditions where Compound 1concentrations were constant, i.e. concentrations of ICI-182780 when 50%of the proliferation of MCS-2 cells was inhibited, were plotted on theisobologram (FIG. 3) constructed in the above-mentioned (2). The resultsare shown in FIG. 5.

When the plots lay below a line of mode I on the isobologram, it isdetermined that the combination treatment had an additive effect. Whenthe plots lay below a line of mode IIa, it is determined that thecombination treatment further had a supra-additive effect.

As shown in FIG. 4, when ICI-182780 was used at constant concentrations,the addition of Compound 1 supra-additively inhibited the cellproliferation.

As shown in FIG. 5, when-Compound 1 was used at constant concentrations,the addition of ICI-182780 supra-additively inhibited the cellproliferation.

EXPERIMENTAL EXAMPLE 2 Proliferation Inhibition of Breast Cancer CellsUsing Combination of Aromatase Inhibitor and Steroid-Sulfatase Inhibitor

Proliferation inhibition of breast cancer cell line (MCS-2) excessivelyexpressing a human steroid-sulfatase by using an aromatase inhibitoralone or a steroid-sulfatase inhibitor alone was compared with thatusing a combination of the steroid-sulfatase inhibitor and the aromataseinhibitor. Vorozole was used as the aromatase inhibitor, and Compound 1was used as the steroid-sulfatase inhibitor.

Medium C containing 10⁻⁸ mol/L estrone sulfate (final concentration) and10⁻⁷ mol/L testosterone (final concentration) was prepared by diluting aDMSO solution containing 10 mmol/L estrone sulfate (Sigma Corp.) and aDMSO solution containing 10 mmol/L testosterone (Sigma Corp.) withmedium A used in Experimental Example 1.

MCS-2 cells were diluted with medium A to 2.5×10⁴ cells/mL, and thenwere inoculated in a 24-well microtiter plate (NUNC) at an amount of 100μL/well. The plate was incubated in an incubator set at 37° C. and ahumidity of 0.95% or more in a 5%-CO₂ atmosphere for 24 hours, and thenthe medium was replaced with fresh medium C or fresh medium A. Medium Ccontained estrone sulfate at a final concentration of 10⁻⁸ mol/L andtestosterone at a final concentration of 10⁻⁷ mol/L. Medium A containedneither estrone sulfate nor testosterone. To each well in which themedium was replaced with medium C, test compound diluted with a medium A[(i) an aromatase inhibitor alone, (ii) a steroid-sulfatase inhibitoralone, or (iii) a combination of the aromatase inhibitor and thesteroid-sulfatase inhibitor] was added, or was not added [(iv)agent-free]. The plate was incubated in an incubator set at 37° C. and ahumidity of 95% or more in a 5%-CO₂ atmosphere for 168 hours. The testcompound were not added to the wells in which the medium was replacedwith medium A (which contained neither estrone sulfate nortestosterone). These wells were incubated under the same conditions asabove and used as controls. After the incubation, the supernatant wascarefully removed such that all the cells retained. Then, the wells werecarefully rinsed with a phosphate buffer (GIBCO) such that all the cellsretained. A solution of 0.25% trypsin (GIBCO) and an aqueous solution of0.02% ethylenediaminetetraacetic acid (EDTA, Wako Pure ChemicalIndustries, Ltd.) were added to the wells to thoroughly suspend thecells. The number of cells in each well was counted with a microcellcounter (Sysmex).

FIG. 6 shows the numbers of MCS-2 cells in the presence of estronesulfate and testosterone, when an aromatase inhibitor (vorozole), asteroid-sulfatase inhibitor (Compound 1), or both vorozole and Compound1 were added (N=3 each).

When Compound 1 was not added, inhibition of the cell proliferation wasvery low regardless of an increase in the concentration of vorozole.That is, the inhibition of the proliferation was able to be observed ata high concentration of 100 nmol/L. On the contrary, when Compound 1 wasadded, significant inhibition of the cell proliferation was observed.

The therapeutic agents and pharmaceutical compositions for the treatmentof hormone-dependent cancers according to the present invention, whichare prepared so as to contain active ingredients from bothsteroid-sulfatase inhibitors and agents for hormone therapy and/oragents for chemotherapy, can be used, administered, or manufactured inthe form of a single preparation or a combination of some preparations.These therapeutic agents in unit dose form are preferable for oral orparenteral (e.g. injection) administration. When the therapeutic agentsare used or administered in combination, they may be used oradministered together or separately at an interval.

These preparations may contain a pharmaceutically acceptable diluent,excipient, disintegrant, lubricant, binder, surfactant, water, saline,vegetable-oil solubilizer, isotonic agent, preservative, or antioxidantin addition to the effective ingredients, and can be manufactured by aconventional process.

In the preparation of tablets, an excipient, e.g. lactose, adisintegrant, e.g. starch, a lubricant, e.g. magnesium stearate, abinder, e.g. hydroxypropyl cellulose, a surfactant, e.g. fatty acidester, a plasticizer, e.g. glycerin, and the like may be used accordingto a conventional process.

In the preparation of injections, water, saline, a vegetable-oil, asolvent, a solubilizer, an isotonic agent, a preservative, anantioxidant, and the like may be used according to a conventionalprocess.

When compound (I), (IA), (IB), and pharmaceutically acceptable saltsthereof are used for the above-mentioned purposes, they may beadministered orally or parenterally such as injections. An effectivedose and frequency of administration depend on the administration formand subject's age, weight, and symptoms. In general, 0.01 to 20mg/kg/day is preferably administered.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of an MTT assay showing the inhibition of MCS-2cell proliferation when the concentrations of ICI-182780 were constantin the range from 0 to 1.801 nmol/L and Compound 1 was sequentiallydiluted (1.5-fold for each dilution) from 3.000 nmol/L to 0.004 nmol/L(N=3 each). The vertical axis of the graph represents a relative valueof the number of MCS-2 cells in each condition to that in the agent-freecondition, which is shown as a relative value (%) of each absorbance. Onthe horizontal axis of the graph, the amounts of Compound 1 (nmol/L) areshown. Plots on the graph represent concentrations (nmol/L) ofICI-182780.

-   -∘-: ICI-182780 free-   -●-: ICI-182780 at a concentration of 0.030 nmol/L-   -⋄-: ICI-182780 at a concentration of 0.051 nmol/L-   -♦−: ICI-182780 at a concentration of 0.084 nmol/L-   --∘--: ICI-182780 at a concentration of 0.140 nmol/L-   -●-: ICI-182780 at a concentration of 0.234 nmol/L-   -□-: ICI-182780 at a concentration of 0.390 nmol/L-   --□--: ICI-182780 at a concentration of 0.649 nmol/L-   -Δ-: ICI-182780 at a concentration of 1.081 nmol/L-   -▴-: ICI-182780 at a concentration of 1.801 nmol/L

FIG. 2 shows the results of an MTT assay showing the inhibition of MCS-2cell proliferation when the concentrations of Compound 1 were constantin the range from 0 to 1.081 nmol/L and ICI-185780 was sequentiallydiluted (1.5-fold for each dilution) from 10.000 nmol/L to 0.014 nmol/L(N=3 each). The vertical axis of the graph represents a relative valueof the number of MCS-2 cells in each condition to that in the agent-freecondition, which is shown as a relative value (%) of each absorbance. Onthe horizontal axis of the graph, the amounts of ICI-182780 (nmol/L) areshown. Plots on the graph represent concentrations (nmol/L) of Compound1 shown below.

-   -∘-: Compound 1 free-   -●-: Compound 1 at a concentration of 0.018 nmol/L-   -⋄-: Compound 1 at a concentration of 0.030 nmol/L-   -♦-: Compound 1 at a concentration of 0.051 nmol/L-   --∘--: Compound 1 at a concentration of 0.084 nmol/L-   --●--: Compound 1 at a concentration of 0.140 nmol/L-   -□-: Compound 1 at a concentration of 0.234 nmol/L    -   --□--: Compound 1 at a concentration of 0.389 nmol/L    -   -Δ-: Compound 1 at a concentration of 0.649 nmol/L    -   -▴-: Compound 1 at a concentration of 1.081 nmol/L

FIG. 3 shows an isobologram for the IC₅₀ value constructed from an IC₅₀value, IC₄₅ value, IC₄₀ value, IC₃₅ value, IC₃₀ value, IC₂₅ value, IC₂₀value, IC₁₅ value, IC₁₀ value, and IC₅ value calculated from theinhibition curves on the MCS-2 cell proliferation shown in FIGS. 1 and 2for both ICI-182780 alone and Compound 1 alone. The vertical axis of thegraph represents a fraction of IC₅₀ of ICI-182780, and the horizontalaxis represents that of Compound 1.

FIG. 4 shows the concentrations (IC₅₀ values) calculated from theinhibition curves shown in FIG. 1 when Compound 1 inhibited 50% of theproliferation of MCS-2 cells under the conditions where theconcentrations of ICI-182780 were constant in the range from 0.030nmol/L to 1.801 nmol/L and Compound 1 was sequentially diluted (1.5-foldfor each dilution) from 3.000 nmol/L to 0.004 nmol/L. The concentrationsof Compound 1 are plotted with symbol ● on the isobologram (FIG. 3).

FIG. 5 shows the concentrations (IC₅₀ values) calculated from theinhibition curves shown in FIG. 2 when ICI-182780 inhibited 50% of theproliferation of MCS-2 cells under the conditions where theconcentrations of Compound 1 were constant in the range from 0.018nmol/L to 1.081 nmol/L and ICI-182780 was sequentially diluted (1.5,fold for each dilution) from 10.000 nmol/L to 0.014 nmol/L. Theconcentrations of ICI-182780 are plotted with symbol ● on theisobologram (FIG. 3).

FIG. 6 shows the inhibition of MCS-2 cell proliferation when acombination of vorozole and Compound 1 was used in the presence ofestrone sulfate and testosterone. The vertical axis of the graphrepresents the number of MCS-2 cells (×10³ cells/mL), and the horizontalaxis represents control and vorozole concentration (nmol/L). The threebars show the results when Compound 1 was added at a concentration of,from the left, 0 nmol/L, 3.0 nmol/L, and 10.0 nmol/L.

BEST MODE FOR CARRYING OUT THE INVENTION

The formulation examples will be illustrated below, however theseexamples are never intended to limit the scope of the present invention.

FORMULATION EXAMPLE 1 Tablet

Tablets having the following composition are prepared according to aconventional procedure. Compound 1 5 mg Lactose 60 mg Potato starch 30mg Polyvinylalcohol 2 mg Magnesium stearate 1 mg Tar pigment smallamount

FORMULATION EXAMPLE 2 Tablet

Tablets having the following composition are prepared according to aconventional procedure. Compound 1 5 mg Tamoxifen 10 mg Lactose 60 mgPotato starch 30 mg Polyvinylalcohol 2 mg Magnesium stearate 1 mg Tarpigment small amount

PREPARATION EXAMPLE 3 Injection

An injection having the following composition is prepared according to aconventional procedure. Compound 1  2 mg D-mannitol 10 mg Hydrocholoricacid solution proper amount Sodium hydroxide solution proper amountInjectable distilled water proper amount

INDUSTRIAL APPLICABILITY

According to the present invention, a therapeutic agent for ahormone-dependent cancer, which comprises (a) a steroid-sulfataseinhibitor and (b) an agent for hormone therapy and/or an agent forchemotherapy, and the like are provided. The above agent shows moreexcellent activity in treating a hormone-dependent cancer than asteroid-sulfatase alone or an agent for hormone therapy and/or an agentfor chemotherapy alone.

1. A therapeutic agent for a hormone-dependent cancer, which comprises (a) a steroid-sulfatase inhibitor; and (b) an agent for hormone therapy and/or an agent for chemotherapy, which may be administered together or separately at an interval.
 2. A method for treating a hormone-dependent cancer, which comprises: administering (a) a steroid-sulfatase inhibitor and (b) an agent for hormone therapy and/or an agent for chemotherapy together or separately at an interval.
 3. A steroid-sulfatase inhibitor, which is used in combination with an agent for hormone therapy and/or an agent for chemotherapy, and which is administered together therewith or separately therefrom at an interval.
 4. A kit for treating a hormone-dependent cancer, which comprises: a first component comprising (a) a steroid-sulfatase inhibitor and a second component comprising (b) an agent for hormone therapy and/or an agent for chemotherapy.
 5. A pharmaceutical composition, which comprises: (a) a steroid-sulfatase inhibitor; and (b) an agent for hormone therapy and/or an agent for chemotherapy.
 6. (canceled)
 7. The therapeutic agent for a hormone-dependent cancer according to claim 1, wherein the steroid-sulfatase inhibitor is a composition comprising, as an active ingredient, a compound represented by Formula (I), Formula (IA), or Formula (IB), or any of respective pharmaceutically acceptable salts thereof, wherein Formula (I), Formula (IA), and Formula (IB) are:

[wherein X represents a phosphorus atom or a sulfur atom, and when X is a phosphorus atom, Y is hydroxy, and when X is a sulfur atom, Y is oxo; R represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or —NR³R⁴ (wherein R³ and R⁴ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted aryl, or R³ and R⁴ are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group); and —O—R² represents a monocyclic alcohol residue or a polycyclic alcohol residue],

(wherein —O—R², R³, and R⁴ have the same meanings as defined above, respectively), and

[wherein R³ and R⁴ have the same meanings as defined above, respectively; R⁵ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, —NR⁶R⁷ (wherein R⁶ and R⁷ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), —OR⁸ (wherein R⁸ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), or —SR^(8A) (wherein R^(8A) has the same meaning as R⁸ defined above)].
 8. The method for treating a hormone-dependent cancer according to claim 2, wherein the steroid-sulfatase inhibitor is a composition comprising, as an active ingredient, the compound represented by Formula (I), Formula (IA), or Formula (IB) or any of respective pharmaceutically acceptable salts thereof, wherein Formula (I), Formula (IA), and Formula (IB) are:

[wherein X represents a phosphorus atom or a sulfur atom, and when X is a phosphorus atom, Y is hydroxy, and when X is a sulfur atom, Y is oxo; R¹ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or —NR³R⁴ (wherein R³ and R⁴ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted aryl, or R³ and R⁴ are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group); and —O—R² represents a monocyclic alcohol residue or a polycyclic alcohol residue],

(wherein —O—R², R³, and R⁴ have the same meanings as defined above, respectively), and

[wherein R³ and R⁴ have the same meanings as defined above, respectively, R⁵ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, —NR⁶R⁷ (wherein R⁶ and R⁷ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), —OR⁸ (wherein R⁸ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), or —SR^(8A) (wherein R^(8A) has the same meaning as R⁸ defined above)].
 9. The steroid-sulfatase inhibitor according to claim 3, wherein the steroid-sulfatase inhibitor is a composition comprising, as an active ingredient, the compound represented by Formula (I), Formula (IA), or Formula (IB) or any of respective pharmaceutically acceptable salts thereof, wherein Formula (I), Formula (IA), and Formula (IB) are:

[wherein X represents a phosphorus atom or a sulfur atom, and when X is a phosphorus atom, Y is hydroxy, and when X is a sulfur atom, Y is oxo; R¹ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or —NR³R⁴ (wherein R³ and R⁴ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted aryl, or R³ and R⁴ are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group); and —O—R² represents a monocyclic alcohol residue or a polycyclic alcohol residue],

(wherein —O—R², R³, and R⁴ have the same meanings as defined above, respectively), and

[wherein R³ and R⁴ have the same meanings as defined above, respectively; R⁵ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, —NR⁶R⁷ (wherein R⁶ and R⁷ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), —OR⁸ (wherein R⁸ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), or —SR^(8A) (wherein R^(8A) has the same meaning as R⁸ defined above)].
 10. The kit for treating according to claim 4, wherein the steroid-sulfatase inhibitor is a composition comprising, as an active ingredient, the compound represented by Formula (I), Formula (IA), or Formula (IB) or any of respective pharmaceutically acceptable salts thereof, wherein Formula (I), Formula (IA), and Formula (IB) are:

[wherein X represents a phosphorus atom or a sulfur atom, and when X is a phosphorus atom, Y is hydroxy, and when X is a sulfur atom, Y is oxo, R¹ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or —NR³R⁴ (wherein R³ and R⁴ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted aryl, or R³ and R⁴ are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group); and —O—R² represents a monocyclic alcohol residue or a polycyclic alcohol residue],

(wherein —O—R², R³, and R⁴ have the same meanings as defined above, respectively), and

[wherein R³ and R⁴ have the same meanings as defined above, respectively R⁵ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, —NR⁶R⁷ (wherein R⁶ and R⁷ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), —OR⁸ (wherein R⁸ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), or —SR^(8A) (wherein R^(8A) has the same meaning as R⁸ defined above)].
 11. The pharmaceutical composition according to claim 5, wherein the steroid-sulfatase inhibitor is a composition comprising, as an active ingredient, the compound represented by Formula (I), Formula (IA), or Formula (IB) or any of respective pharmaceutically acceptable salts thereof, wherein Formula (I), Formula (IA), and Formula (IB) are:

[wherein X represents a phosphorus atom or a sulfur atom, and when X is a phosphorus atom, Y is hydroxy, and when X is a sulfur atom, Y is oxo; R¹ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or —NR³R⁴ (wherein R³ and R⁴ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted aryl, or R³ and R⁴ are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group); and —O—R² represents a monocyclic alcohol residue or a polycyclic alcohol residue],

(wherein —O—R², R³, and R⁴ have the same meanings as defined above, respectively), and

[wherein R³ and R⁴ have the same meanings as defined above, respectively; R⁵ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, —NR⁶R⁷ (wherein R⁶ and R⁷ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), —OR⁸ (wherein R⁸ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), or —SR^(8A) (wherein R^(8A) has the same meaning as R⁸ defined above)]. 12-24. (canceled)
 25. The therapeutic agent for a hormone-dependent cancer according to claim 1, wherein the agent for hormone therapy is one or more selected from the group consisting of an antiestrogen agent, an aromatase inhibitor, an antiandrogen agent, a preparation comprising progesterone, and a preparation comprising a luteinizing hormone-releasing hormone (LH-RH) agonist.
 26. The method for treating a hormone-dependent cancer according to claim 2, wherein the agent for hormone therapy is one or more selected from the group consisting of an antiestrogen agent, an aromatase inhibitor, an antiandrogen agent, a preparation comprising progesterone, and a preparation comprising a LH-RH agonist.
 27. The steroid-sulfatase inhibitor according to claim 3, wherein the agent for hormone therapy is one or more selected from the group consisting of an antiestrogen agent, an aromatase inhibitor, an antiandrogen agent, a preparation comprising progesterone, and a preparation comprising a LH-RH agonist.
 28. The kit for treating according to claim 4, wherein the agent for hormone therapy is one or more selected from the group consisting of an antiestrogen agent, an aromatase inhibitor, an antiandrogen agent, a preparation comprising progesterone, and a preparation comprising a LH-RH agonist.
 29. The pharmaceutical composition according to claim 5, wherein the agent for hormone therapy is one or more selected from the group consisting of an antiestrogen agent, an aromatase inhibitor, an antiandrogen agent, a preparation comprising progesterone, and a preparation comprising a LH-RH agonist.
 30. (canceled)
 31. The therapeutic agent for a hormone-dependent cancer according to claim 1, wherein the agent for hormone therapy is an antiestrogen agent and/or an aromatase inhibitor.
 32. The method for treating a hormone-dependent cancer according to claim 2, wherein the agent for hormone therapy is an antiestrogen agent and/or an aromatase inhibitor.
 33. The steroid-sulfatase inhibitor according to claim 3, wherein the agent for hormone therapy is an antiestrogen agent and/or an aromatase inhibitor.
 34. The kit for treating according to claim 4, wherein the agent for hormone therapy is an antiestrogen agent and/or an aromatase inhibitor.
 35. The pharmaceutical composition according to claim 5, wherein the agent for hormone therapy is an antiestrogen agent and/or an aromatase inhibitor.
 36. (canceled) 